Juvenile spondyloarthropathies (SpAs) differ from juvenile rheumatoid arthritis (JRA) in terms of genetic predisposition, pathogenesis, and outcome with a significant proportion developing progressive axial involvement known as ankylosing spondylitis (AS), yet they are difficult to distinguish from other forms of JRA at the time of diagnosis. One genetic factor, HLA-B27, has been linked to disease susceptibility and pathogenesis. Although our understanding of the physiological function of this molecule has not yielded a pathogenic mechanism, growing evidence supports our novel hypothesis that misfolding and the generation of an ER stress response may be involved. This proposal, and indeed the entire Program Project (P01), seeks to utilize methods that exploit human genome sequence information and microarray technology to comprehensively evaluate peripheral blood and synovial fluid mononuclear cell (PBMC) RNA expression differences in various forms of juvenile arthritis. From disease-specific differences profiles will be developed that can be used at the bedside and at the bench for diagnostic clarification, and to evaluate molecular mechanisms of pathogenesis. In this proposal (project by Colbert) we will examine gene expression profiles in patients with recent onset juvenile SpAs using samples collected through a Tissue Repository Core and used to establish a comprehensive New Onset Data Set (NODS) shared by all of the projects. Using the NODS we will interact extensively with the Informatics Core to establish a unique SpA-related gene expression profile, and further distinguish undifferentiated from progressive disease with the aim of establishing predictors of outcome. PBMC cell populations thought to be important in the pathogenesis of SpAs will be examined in both an unbiased and hypothesis-directed manner, looking to confirm key elements of the ER stress response found in the preliminary analyses. We will monitor expression differences that occur during the response to therapy with TNF inhibitors to provide a greater focus on genes that are critical to pathogenesis. The success of individual projects in this P01 will be greatly enhanced by the programmatic aspects of this proposal, in particular the generation and analysis of the NODS as well as ongoing collaborations. Validated data will be made available to the research community at large, with the potential to make a significant impact on future pediatric rheumatology research. It is anticipated that these studies will lead to better diagnostic and eventually therapeutic tools for juvenile SpAs.